674 replies to this topic

[Turnbuckle]

Aβ plaques are reported to be the initiators of AZ, which also involve tau as a secondary aspect. In the following experimental protocol, HEPPS and taurine are used to dissolve Aβ plaques and oleuropein renders the dissolved portion non-toxic. This is an experimental protocol I first used on myself. I'm a few years from 70 and was having symptoms, in particular that I could no longer type anything without having it full of errors. This had been building up for a year, and possibly longer. Within days most of that went away, and it has continued to improve for 2 months.

 

All items are available from Amazon in the US —

 

 

Alzheimer's protocol — experimental

Once a day for several months —

 

HEPPS [aka, EPPS] — 1g (1/4 level teaspoon)

Taurine — 8g (2 level teaspoons)

Oleuropein — 200 mg

Vitamin C — 2g

 

 

References—

 

Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis.

Aβ is upstream of tau in AD pathogenesis and triggers the conversion of tau from a normal to a toxic state, but there is also evidence that toxic tau enhances Aβ toxicity via a feedback loop. Because soluble toxic aggregates of both Aβ and tau can self-propagate and spread throughout the brain by prionlike mechanisms, successful therapeutic intervention for AD would benefit from detecting these species before plaques, tangles, and cognitive impairment become evident and from interfering with the destructive biochemical pathways that they initiate.

https://www.ncbi.nlm...pubmed/24493463

 

EPPS reduces Aβ-aggregate-induced memory deficits in mice

Previously, we reported a series of small ionic molecules that could accelerate the formation of Aβ aggregates in vitro. Unexpectedly, in addition to the compounds facilitating Aβ aggregation, we identified six small molecules that inhibited the formation of Aβ oligomers and fibrils13. In the current study, we tested whether these molecules could affect AD-like cognitive impairments of rodents. For this purpose, we induced memory deficits in 8.5-week-old Imprinting Control Region (ICR) mice (male, n=9–10 per group) by injecting Aβ42 aggregates (Fig. 1a,b) into the intracerebroventricular region14. This Aβ-infusion model allowed us to control the onset of abnormal Aβ deposition before or after the administration of our compounds. Among the six orally administered molecules, only 4-(2-hydroxyethyl)-1-piperazinepropanesulphonic acid (EPPS) ameliorated AD-like phenotypes in our mouse model.

https://www.nature.com/articles/ncomms9997

 

Taurine in drinking water recovers learning and memory in the adult APP/PS1 mouse model of Alzheimer's disease

We orally administered taurine via drinking water to adult APP/PS1 transgenic mouse model for 6 weeks. Taurine treatment rescued cognitive deficits in APP/PS1 mice up to the age-matching wild-type mice in Y-maze and passive avoidance tests without modifying the behaviours of cognitively normal mice.

https://www.nature.com/articles/srep07467

 

Noncovalent Interaction Between Amyloid-β-Peptide (1-40) and Oleuropein Studied by Electrospray Ionization Mass Spectrometry

The successful detection of the noncovalent complex between Aβ and OE [Oleuropein] could be invaluable in a series of studies focused on screening the ability of several bioactive phytochemicals in terms of complexating Aβ and Aβox and “locking” them in a non-toxic conformation, thus acting as potential anti-amyloidogenic agents. This may offer an ideal protective alternative against Aβ toxicity.

http://www.sciencedirect.com/science/article/pii/S104403050501024X?via%3Dihub

 

Preventive and therapeutic potential of ascorbic acid in neurodegenerative diseases.

Ascorbic acid acts mainly by decreasing oxidative stress and reducing the formation of protein aggregates, which may contribute to the reduction of cognitive and/or motor impairments observed in neurodegenerative processes.

https://www.ncbi.nlm.nih.gov/pubmed/28980404

Edited by Turnbuckle, 11 January 2018 - 08:52 PM.

[High_Probability]

Turnbuckle,

 

What brand of Oleuropein are you using?  I don't see any products that are 100% Oleuropein.  Did you purchase an Olive Leaf  extract with the highest Oleuropein content (but that still has all of the other phytochemicals)?

Edited by High_Probability, 11 January 2018 - 10:41 PM.

[Turnbuckle]

Turnbuckle,

 

What brand of Oleuropein are you using?  I don't see any products that are 100% Oleuropein.  Did you purchase an Olive Leaf  extract with the highest Oleuropein content (but that still has all of the other phytochemicals)?

 

This was Swanson's brand with 20% oleuropein. They don't say what the rest of it is. Note that oleuropein lowers blood pressure, as does taurine, so keep that in mind if taking BP medication.

[ceridwen]

Many thanks

[ceridwen]

I'm sure that mitochondria play a very important role as well.

[ceridwen]

Where can I buy EPPS?

[Turnbuckle]

Where can I buy EPPS?

 

HEPPS/EPPS is widely available in the US and UK--it's a common biological buffer--but most chem suppliers aren't going to ship to a home address, so likely you will have to go through a business or university. In the US it can be shipped to a home address if you buy it from Amazon. Another option is China, assuming you want a few kilos.

[tunt01]

Here's 100g of HEPPS available on Amazon

[sensei]

I would up the Vitamin C to 6 grams Liposomal -- so it more readily crosses the BBB, 2 ghrams 3 times a day

[tunt01]

Isn't a protocol withTaurine and EPPS redundant?  Isn't EPPS basically a Taurine derivative designed for a longer half-life in the body?

Edited by prophets, 12 January 2018 - 03:06 PM.

[Turnbuckle]

Isn't a protocol withTaurine and EPPS redundant?  Isn't EPPS basically a Taurine derivative designed for a longer half-life in the body?

 

Taurine and HEPPS are similar in that they both have sulfonic acid groups at one end*, but while taurine appears to have a short half life of about one hour, HEPPS appears considerably longer (though I've not seen it expressed in hours). Oleuropein also has an ill defined half life, though it appears to be several hours judging by its effect on my BP. So there's an overlap, and likely HEPPS is the preferable of the two if only one were to be used.

 

The experiments with mice used used these things in water, so the dosing was more or less continuous.

 

*Similar molecules are known. HEPES is almost identical to HEPPS, for instance, but I've seen one report that HEPES may compact plaques, which is the opposite of what you want. Many others are available, but without study they could be dangerous to use. Small chemical differences can produce opposite effects.

 

Plasma taurine concentration peaked to 59.0–112.6 mg/L (mean 86.1 ± 19.0) at 1–2.5 hr of study, plasma elimination half-life ranged from 0.7 to 1.4 hr (mean 1.0 ± 0.3)

https://www.ncbi.nlm...les/PMC3275936/

 

 

We found that the brain concentration of EPPS (10 mg kg−1 per day) reached its plateau (7.52 ng g−1) within 72 hours

https://www.nature.c...cles/ncomms9997

 

 

 

Edited by Turnbuckle, 12 January 2018 - 04:29 PM.

[ceridwen]

Any chance of a group buy?

[Daniel Cooper]

Any chance of a group buy?

 

 

I'm not seeing anything on the list that isn't readily available.  Why would we be interested in a group buy?

[Daniel Cooper]

You've several good things for Aβ plaques, but perhaps you might want to add some niacinamide for tau protein tangles?

   

 

 

 

[Turnbuckle]

You've several good things for Aβ plaques, but perhaps you might want to add some niacinamide for tau protein tangles?

 

 

I wasn't going to post this yet, but what the hell--

 

 

Tau protocol

 

While Aβ plaques are the first half of AZ, the second half is p-tau, which is a phospho-species of tau that is responsible for the fibril tangles inside nerve cells. So the complete treatment is getting rid of the plaques that start it all, and then getting rid of the tangles that appear to be a secondary result of the plaques.

 

I don’t know if the Aβ and tau treatments can be done at the same time, but probably so. The approach for tau is the same as I proposed in the OP for Aβ — dissolve and detoxify.

 

Detoxify: It’s already known that vitamin B3 (as nicotinamide) will reduce p-tau, increase tau stability, and restore mental capacity of mice with an AZ model of the disease.

 

 

Nicotinamide selectively reduces a specific phospho-species of tau (Thr231) that is associated with microtubule depolymerization . . . These preclinical findings suggest that oral nicotinamide may represent a safe treatment for AD and other tauopathies . . .

 

https://www.ncbi.nlm...les/PMC2617713/

 

 

 

Dissolve: But is nicotinamide going to be enough? Some years ago researchers discovered they could dissolve tau tangles with the old drug methylene blue (MB), which they branded in the reduced (and colorless) form as Rember. Unfortunately it failed in Stage 3 trials, as it showed no advantage over placebo. Which isn’t surprising. Dissolve defective tau and let it reform, and tangles could reform as well. Even worse tangles. I experimented with a dose of more than 100mg MB some years ago, and had bad results. I had to take it again along with niacin to get back to baseline. But niacin has a short half-life, so it would be better to take it with nicotinamide instead, along with a dosage of MB that doesn’t dissolve excessive amounts of p-tau. Go slow, in other words.

 

I'm trying this now with 50mg reduced MB and 1g nicotinamide every 5 hours for 24 hours. I'll post the results tomorrow or the next day.

 

One source of MB is the Kordon brand solution available for aquarium use. It is 2.3% MB, thus 44 drops will give you 50mg. To reduce it, place 1 gram of Vitamin C powder at the bottom of a small glass and add the MB dropwise onto the powder. In about 15 minutes the color will disappear and you can add fruit juice and drink it down. Be careful, as even though colorless, it will eventually oxidize and stain anything it touches. The blue color is difficult to remove.

 

This will also turn your urine either green or blue for about 24 hours, so top up the nicotinamide during this time as mentioned above—1g every 5 hours or so. 

 

Again, this is experimental and the experiment is ongoing.

 

 

Edited by Turnbuckle, 12 January 2018 - 08:06 PM.

[Daniel Cooper]

Excellent.  

 

BTW - what's a safe dose range for HEPPS?  LD50?

 

 

 

[Turnbuckle]

Excellent.  

 

BTW - what's a safe dose range for HEPPS?  LD50?

 

The LD50 for taurine is believed to be above 7g/kg, and HEPPS appears to be similarly nontoxic--

 

 

EPPS is orally safe and penetrates the blood–brain barrier

Before conducting further in vivo studies of therapeutic potentials, we measured the toxicity and pharmacokinetics profiles of EPPS. Toxicity and pharmacokinetics are crucial features of AD therapeutics, as long-term treatment is often required. To examine whether EPPS elicits toxic effects when orally administered, we included EPPS in drinking water for wild-type (WT) mice (4-week-old, male, n=6 per group) to determine the half-maximal lethal dosage (LD50). Lethal toxicity was measured based on mortality, changes in body weight and hair loss observed over a 2-month period. The oral administration of EPPS did not cause any toxicity up to 2,000 mg kg−1 per day of administration (LD50>2,000 mg kg−1 per day). 

https://www.nature.c...cles/ncomms9997

 

[Turnbuckle]

 

 

 

 

I'm trying this now with 50mg reduced MB and 1g nicotinamide every 5 hours for 24 hours. I'll post the results tomorrow or the next day.

 

 

 

 

 

 

The initial effect was a slight but definite lowering of cognition and memory below baseline for about ten hours, after which it drifted back up to baseline. It might even be a bit above, but I'm not going to claim that until I see more definitive results. Next trial will be next week with 75mg MB and .5g nicotinamide every 5 hours. This is a 50% bump to the MB level and a 50% cut to the nicotinamide level. I'm cutting nicotinamide as I find 1g a bit unpleasant when used alone (ie, without ribose).

[8bitmore]

It may well be worthwhile adding a source of Lithium to the protocol Turnbuckle outlined in the thread-starter post.  There's very good evidence that Lithium inhibits the GSK-3 enzyme which prompts phosphate to bind to tau proteins and thus forming tangles. I've used to orotate and aspartate versions and not personally sure which form is best (or if there's even a difference).

 

http://www.nature.co...ws040726-4.html

https://www.ncbi.nlm...pubmed/20110614

https://www.scienced...014579397006881

 

And hey: quality thread, I appreciate the shared information within it, thanks

 

[tunt01]

One strategy for preventing Alzheimer's might be salicylate or salsalate, which inhibits p300 behavior.

 

As Alzheimer's is a tauopathy, either preventing phospho-tau (lithium, etc.) or promoting degradation of phospho tau (turnover) is critical for prevention or arresting the process.  Min, et al (Min 2010) found that tau is acetylated by p300, an acetyltransferase.  And the acetylation of tau by p300 ultimately inhibits the degradation as Min states:

 

 

 

 

How might elevated tau acetylation lead to higher levels of p-tau? Acetylation of lysines can preclude its ubiquitination and stabilize proteins that are normally degraded by the UPS, including p53 (Ito et al., 2002), Runx3 (Jin et al., 2004), β-catenin (Ge et al., 2009), and other regulatory factors (Caron et al., 2005). Since tau is ubiquitinated and the degradation of tau, especially p-tau, involves the proteasome-mediated pathway (Petrucelli et al., 2004; Tan et al., 2008), we hypothesized that acetylation precludes tau ubiquitination and suppresses its degradation.

 

 

 

This is consistent with typical AD pathologies that show a reduction in SIRT1, an HDAC the inhibits p300 activity.  Min demonstrated further that SIRT1 deacetylates tau in vitro and in vivo.  SIRT1 deficiencies are common in Alzheimer's (Julien 2009) and an early event in the process (Min 2010, Fig 8D).

 

 

 

It also might explain why the broader implications of exercise, autophagy, excessive caloric intake and alzheimer's being a type 3 diabetes are metabolically intertwined as an underpinning for the disease outcome.  Inhibition of p300 via metabolites like spermidine results in the induction of autophagy.  (Pietrocola 2015)

 

 

Broadly speaking, strategies that upregulate SIRT1 via exercise, fasting, NR supplementation should prevent p300 driven acetylated tau and promote tau turnover via UPS/ubquination.

 

The paper that really caught my eye on this entire matter was Min, et al 2015, where they had an intervention of salicylate.  They specifically target Lysine 174 acetylation in Tau and show that salicylate improved tau turnover and inhibited acetylation of tau.  Acetylation at K174 blocks ubiquination and autophagic processes, but this is restored by salicyate.

 

I thought this was particularly interesting because Darryl and others have cited salicylate/aspirin as an AMPK activator and the prevailing view that aspirin is longevity inducing.  Min's experiment used a mutant form of L174Q, which mimicking acetyl tau and showed reduced tau clearance:

 

Indeed, K174Q and K174R mutants enhance the formation of dimeric tau, which could be neurotoxic. Aberrant cell-cycle reentry iduced by high levels of h-tau25 could also contribute to neurodegeneration in mice injected with AAV-K174Q or -K174R. Our results also support a role of ac-K174 in tau homeostasis. Expressing K174Q, not K174R, leads to longer half-life in primary neurons and aberrant accumulation in vivo, showing that K174 acetylation per se, not the blockage of K174 polyubiquitination, impairs tau clearance. Interestingly, a recent mass-spec study provided clear evidence that acetylation and ubiquitination occurs on the same lysine residues, supporting an intimate relationship of these two modifications37.

One of the main enzymes that acetylate tau is p30014, which can be inhibited by SS/SSA, an ancient drug commonly used as an NSAID. Pharmacokinetically, SSA is quickly metabolized into its active component, salicylate. Unlike salicylate, aspirin (acetyl salicylate) elevates ac-tau in cultured neurons (not shown). SSA and aspirin had been widely used NSAIDs to treat rheumatoid arthritis and related illnesses in the past decades, presumably via inhibiting cyclo-oxygenases (COX)38. Interestingly, patients taking NSAIDs, including salicylate and derivatives, had a reduced risk of AD39. 

 

 

 

 

 

Min closes out with some comments on aberrant p300 behavior, salicylate dosing and study relevance:

 

Our study provides first proof-of-principle evidence that partial p300 inhibitor could be used to treat tauopathies. Since p300 is important for many biological functions, completely inhibiting it could cause serious side effects. However, a recent study showed that p300 activity is aberrantly elevated in AD brains40. Identified as one of the top dysregulated pathways in AD, aberrantly activated p300 could underlie hyperacetylation of tau in tauopathies40. In moderate and severe AD cases, p300 activities were significantly higher in the CA1 region, where activated p300 and p-tau were colocalized40. p300 activity was also elevated in aged PS19 brains. Thus, partially inhibiting p300 could normalize its aberrant activation and suppress hyperacetylation of its substrates, including tau. Indeed, the remarkable protection of SSA against tau-mediated cognitive deficits and degeneration is unprecedented and could have important clinical implications. Even after disease onset in PS19 mice, SSA treatment improved spatial memory, reduced NFT formation, and abolished hippocampal atrophy, which is associated with increased risk for conversion from mild cognitive impairment to AD46–48. Importantly, the human equivalent dose of 225 mg/kg in the current study is ~1350 mg/day for a 75 kg person49, lower than the dose typically prescribed to human patients (3000 mg/day). Our study supports clinical evaluation of SSA and its derivatives as therapies in human tauopathies.

 

 

 

 

 

 

Julien C, Tremblay C, Émond V, et al. SIRT1 Decrease Parallels the Accumulation of tau in Alzheimer Disease. Journal of neuropathology and experimental neurology. 2009;68(1):48. doi:10.1097/NEN.0b013e3181922348.

 

Min S-W, Cho S-H, Zhou Y, et al. Acetylation of Tau Inhibits Its Degradation and Contributes to Tauopathy. Neuron. 2010;67(6):953-966. doi:10.1016/j.neuron.2010.08.044.

 

Min, S., Chen, X., Tracy, T., Li, Y., Zhou, Y., & Wang, C. et al. (2015). Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Nature Medicine, 21(10), 1154-1162. doi:10.1038/nm.3951

 

Pietrocola, F., Lachkar, S., Enot, D., Niso-Santano, M., Bravo-San Pedro, J., & Sica, V. et al. (2014). Spermidine induces autophagy by inhibiting the acetyltransferase EP300. Cell Death & Differentiation, 22(3), 509-516. doi:10.1038/cdd.2014.215

Edited by prophets, 16 January 2018 - 03:04 PM.

[Mind]

Dissolve. Sounds good, however, what happens to the by-products after the A-beta and tau are "dissolved"? Do they leave the brain?

 

For removal of A-beta, why not just use one of the (several?) drugs that have already been tested in humans and proven to work (dissolving A-beta)? I get it that these are proprietary/patented, but for the right price, I am sure one could procure some.

[Turnbuckle]

Dissolve. Sounds good, however, what happens to the by-products after the A-beta and tau are "dissolved"? Do they leave the brain?

 

For removal of A-beta, why not just use one of the (several?) drugs that have already been tested in humans and proven to work (dissolving A-beta)? I get it that these are proprietary/patented, but for the right price, I am sure one could procure some.

 

Not just dissolve, but detoxify. 

 

As for drugs that dissolve A-beta, do you have a preference for drugs sold by big pharma? And if so, can you recommend such a drug?

[tunt01]

'Dissolving' abeta would occur via one of two pathways:  1) enzymatic degradation (neprilysin, IDE, matrix metalloproteinases, etc.) or 2) autophagic degradation of Abeta in microglia. 

 

1.  Enzymatic Degradation

 

Insulin Degrading Enzyme (IDE) is the primary enzymatic degradation of abeta.  IDE preferentially targets insulin, and secondarily targets abeta.  Given this preference, it's important to keep insulin low at various points in the day and not constantly stimulate insulin, thus allowing IDE freedom to clean up abeta.  IDE only degrades abeta in monomer form, so the previous suggestion by Turnbuckle of Taurine/EPPS to break up abeta back into monomeric form from aggregates, could be useful here.

 

2.  Autophagic degradation

 

My first thought on a pharmaceutical approach to autophagic degradation would be to turn to the nilotinib thread here on longecity.  I'd have to go back and look at the research/my notes, but I'm pretty sure that drug should stimulate parkin mediated autophagy that ultimately reduces abeta load in the brain.

 

 

[Mind]

Solanezumab dissolves a-beta...but failed to show cognitive improvement within test subjects that already had mild dementia. However, if your goal is only to reduce a-beta build up (which seems like a good idea, since we are not born with a brain full of disruptive aggregates), then maybe it would work.

[Turnbuckle]

Solanezumab dissolves a-beta...but failed to show cognitive improvement within test subjects that already had mild dementia. However, if your goal is only to reduce a-beta build up (which seems like a good idea, since we are not born with a brain full of disruptive aggregates), then maybe it would work.

 

 

No anti-Aβ drugs have proven successful in trials. Part of the problem is that big pharma has been looking for a single patentable silver-bullet drug that can make them billions. But for the great majority that is not going to work, because few of these groups are looking at both Aβ and tau.

 

(As for tau, I did a second try with MB and nicotinamide--re post 18. This time I found no change from baseline, either during or afterward, which suggests that I didn't have much defective tau to begin with. The large amount of nicotinamide I took over the previous year in my mito protocol was likely responsible for that, while my symptoms were coming from Aβ.)

 

The drug you mentioned, Solanezumab, isn't available and would likely be rather pricey if it was. I believe that the simple two pronged approach above is potentially the cure for many people, at low cost and high safety--

 

HEPPS costs about a dollar a day for a daily dose of one gram, and in mice no toxicity was found up to 2g/kg-day

Taurine powder cost 40 cents for 8 grams, and while LD50 is unknown, it is > 7/kg for mice

Oleuropein cost for 200 mg is about 80 cents/day and toxicity is low: > 3g/kg

 

So a little over $2 a day to deal with Aβ, and even less to deal with tau, esp. as you wouldn't use it every day. In fact, I expect that after a few months of both, the average person could coast for years as these things take years to build up and become symptomatic.

Edited by Turnbuckle, 17 January 2018 - 07:47 PM.

[tunt01]

 

 

No anti-Aβ drugs have proven successful in trials. Part of the problem is that big pharma has been looking for a single patentable silver-bullet drug that can make them billions. But for the great majority that is not going to work, because few of these groups are looking at both Aβ and tau.

 

 

 

I thought aducanumab was successful.  Looks like they are going forward w/ Stage 3 clinicals.

[Turnbuckle]

 

 

 

No anti-Aβ drugs have proven successful in trials. Part of the problem is that big pharma has been looking for a single patentable silver-bullet drug that can make them billions. But for the great majority that is not going to work, because few of these groups are looking at both Aβ and tau.

 

 

 

I thought aducanumab was successful.  Looks like they are going forward w/ Stage 3 clinicals.

 

 

Depends what you mean by successful.

 

Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aβ in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating-Sum of Boxes and Mini Mental State Examination scores. 

https://www.ncbi.nlm...pubmed/27582220

 

 

 

Though this failure to reverse the clinical decline may have more to do with their attacking only the Aβ aspect and not the tau. Still, after one year? The removal of Aβ with HEPPS, while with mice, went much faster than that. See Fig. 4 in this paper.

[ceridwen]

I can't get HEPPS

[ceridwen]

Amazon.com doesn't ship to the uk

[ceridwen]

Amazon.com doesn't ship to the uk
What do you think of the Bredesen Protocol?
What do you think of the Bredesen Protocol?